We propose a discovery project that aims to identify and compare potential blood based biomarkers and risk factors for lung cancer among women smokers and never smokers. While most cases of lung cancer are attributable to smoking, a significant percentage is not attributable to smoking and in the United States some 15% (12,265 cases) to 25% (20,442 cases) of women with lung cancers are never smokers and there is a pressing need to develop a better understanding of this disease and means to detect it early. The Women's Health Initiative has excellent and unique resources for the proposed studies given the size of the WHI cohorts. We propose to rely on in-depth quantitative proteomic analysis of plasma specimens collected as part of the observational study (OS). A total of 907 lung cancer cases have been diagnosed in the WHI cohort through 8/15/2007. Published data indicate that 16% of these cases were diagnosed among never smokers. For discovery of early detection biomarkers we wil constitute 10 pools of 10 smoker cases each (with controls matched 1: 1 on age and smoking history) and 5 pools of 10 never smoker cases each (with matched controls, diagnosed within two years of a blood draw. For discovery of risk biomarkers we wil constitute 10 pools of 16 smoker cases each (with matched controls) and 5 pools of 16 never smoker cases each (with matched controls) diagnosed between 2 and six years after a blood draw. One case and one matched control plasma pool are subjected to isotopic protein labeling prior to extensive fractionation and in-depth quantitative mass spectrometric analysis of individual fractions resulting in a large database of identified and quantified proteins in various fractions and various pools that wil be subjected to statistical analysis to identify potential early detecion markers and protein-disease associations. Hypotheses to be tested include evidence of hormone replacement therapy (HRT) effect on the risk of smoker and never smoker lung cancer and chronic inflammation as a risk factor for lung cancer. This proposal wil take advantage of ongoing proteomic studies by this group using WHI specimens and experience and results obtained toward identifying protein-disease associations that predict major health benefits and risks for HRT and studies aimed at identifying potential biomarkers for the early detection of breast cancer.